FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein

Abstract

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Aβ₄₀ or Aβ₄₂ levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome. Alzheimer disease (AD) and fragile X syndrome (FXS) are devastating neurological disorders associated with synaptic dysfunction resulting in cognitive impairment and behavioral deficits. Despite these similar endpoints, the pathobiology of AD and FXS have not previously been linked. We have established that translation of amyloid precursor protein (APP), which is cleaved to generate neurotoxic βamyloid, is normally repressed by the fragile X mental retardation protein (FMRP) in the dendritic processes of neurons. Activation of a particular subtype of glutamate receptor (mGluR₅) rapidly increases translation of APP in neurons by displacing FMRP from a guanidine-rich sequence in the coding region of APP mRNA. In the absence of FMRP, APP synthesis is constitutively increased and nonresponsive to mGluR-mediated signaling. Excess APP is proteolytically cleaved to generate significantly elevated βamyloid in multiple mutant mouse strains lacking FMRP compared to wild type. Our data support a growing consensus that FMRP binds to guanine-rich domains of some dendritic mRNAs, suppressing their translation and suggest that AD (neurodegenerative disorder) and FXS (neurodevelopmental disorder) may share a common molecular pathway leading to the overproduction of APP and its protein-cleaving derivatives.